Millions of people die every year as a direct result of dehydration, with countless others suffering physiologic and cognitive impairment. While providing safe drinking water is the ultimate solution, this is not always immediately possible (e.g., illness, water contamination, natural disasters, etc.). Despite decades of work aimed at understanding the pathophysiology of dehydration, the existence of dehydration-related morbidity and mortality exists suggests that alternative research strategies promoting new understanding are urgently needed. One such alternative strategy includes the elucidation of the genomic architecture of dehydration. Indeed, understanding architecture is, prima facie, relevant to human health and medicine as the genomic mechanisms underlying disease phenotypes often suggest novel treatment strategies (e.g., in diabetes, many cancers, and coronary artery disease). The proposed multidisciplinary research approach aims to characterize the physiology and genomic architecture of dehydration tolerance in an emerging rodent model in laboratory and wild animals. Specifically, physiology will be characterized, and previously identified pathways related to metabolic water production in renal vasoconstriction will be pharmacologically and genetically manipulated. Field studies that leverage the fact that wild cactus mice exist in both desert and non-desert locations in Southern California. Natural variation in drought tolerance exists. Exome capture and RADseq sequencing will be performed on all animals from multiple populations, and a population genomic approach will be used to identify genes and genomic regions likely responsible for variation in drought tolerance. Together, the proposed work will provide important and novel insights into a condition impacting millions of individuals. Indeed, understanding the physiology and genomic underpinnings of dehydration is the critical first step in the pathway leading to treatments and interventions.